The aim of this study was to develop and evaluate ondansetron gels for transdermal effect using in-vitro and ex-vivo permeation methods.  Ondansetron gels were prepared using; sodium carboxymethyl cellulose (Na CMC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sodium alginate, and pluronic F- 127 as gelling polymers. Polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG) 400 were used as solubility enhancers. Oleic acid, ethyl alcohol, menthol, isopropyl myristate and propylene glycol were evaluated as penetration enhancers. The effect of the employed gel bases and permeation enhancers on the physicochemical characterization and drug permeation through cellophane membrane and rat skin were determined.  The results showed that both polymers and their concentrations affect the permeation of drug, by increasing the polymer concentration in the formulation, viscosity increased and invitro permeation of ondansetron decreased. Formula containing 16% of hydroxyl propyl cellulose with PVP/PEG400 (1.5/5% w/w) showed the highest amount permeation (95% over a 6 hrs period) through cellophane membrane. Both formulae containing 16% of hydroxyl propyl cellulose with PVP/PEG400 (1.5/5% w/w) and 7% of sodium alginate with PVP/ PEG400 (1.5/5% w/w) showed the best permeation through rat skin (amount permeated about 345.06 µg/cm2) over a 6-hr period. PVP/PEG400 (1.5/5% w/w) showed the optimum solubilization enhancement.